Compositions and methods for sublingual delivery of nicotine

ABSTRACT

Disclosed herein are compositions and methods for oral delivery of nicotine and nicotine derivatives. In one embodiment the nicotine is delivered in an oral packets, pouches, or sachets.

FIELD

Disclosed herein are compositions and methods for oral delivery ofnicotine and nicotine derivatives. In one embodiment the nicotine isdelivered in an oral packets, pouches, or sachets.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a plot of the individual plasma concentrations (ng/mL) forNicotine versus time (hour) after buccal administration of the nicotinebenzoate control composition disclosed in TABLE I in male Beagle dogs.

FIG. 2 is a plot of the mean plasma concentration (ng/mL) for Nicotineversus time (hour) after buccal administration of nicotine benzoatecontrol composition disclosed in TABLE I in male Beagle dogs.

FIG. 3 is a plot of the individual plasma concentrations (ng/mL) forNicotine versus time (hour) after buccal administration of the disclosednicotine benzoate composition disclosed in Table II (4 mg) in maleBeagle dogs.

FIG. 4 is a plot of the mean plasma concentration (ng/mL) for Nicotineversus time (hour) after buccal administration of the disclosed compoundin Table II (4 mg) in male Beagle dogs.

FIG. 5 is a plot of the individual plasma concentrations (ng/mL) forNicotine versus time (hour) after buccal administration of the nicotinepolacrilex control composition disclosed in TABLE III (4 mg) in maleBeagle dogs (Group 3).

FIG. 6 is a plot of the mean plasma concentration (ng/mL) for Nicotineversus time (hour) after buccal administration of the nicotinepolacrilex control composition disclosed in TABLE III (4 mg) in MaleBeagle dogs (Group 3)

FIG. 7 is a plot of the individual plasma poncentrations (ng/mL) forNicotine versus time (hour) after buccal administration of the nicotinepolarcilex composition disclosed in TABLE VI (4 mg) in male Beagle dogs(Group 4).

FIG. 8 is a plot of the mean plasma concentration (ng/mL) for Nicotineversus time (hour) after buccal administration of the nicotinepolarcrilex composition disclosed in TABLE VI (4 mg) in male Beagle dogs(Group 4).

DETAILED DESCRIPTION OF THE DISCLOSURE

The materials, compounds, compositions, articles, and methods describedherein may be understood more readily by reference to the followingdetailed description of specific aspects of the disclosed subject matterand the Examples included therein.

Also, throughout this specification, various publications arereferenced. The disclosures of these publications in their entiretiesare hereby incorporated by reference into this application in order tomore fully describe the state of the art to which the disclosed matterpertains. The references disclosed are also individually andspecifically incorporated by reference herein for the material containedin them that is discussed in the sentence in which the reference isrelied upon.

General Definitions

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings:

All percentages, ratios and proportions herein are by weight, unlessotherwise specified. All temperatures are in degrees Celsius (° C.)unless otherwise specified.

The terms “a” and “an” are defined as one or more unless this disclosureexplicitly requires otherwise.

Ranges may be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint.

The terms “comprise” (and any form of comprise, such as “comprises” and“comprising”), “have” (and any form of have, such as “has” and“having”), “include” (and any form of include, such as “includes” and“including”) and “contain” (and any form of contain, such as “contains”and “containing”) are open-ended linking verbs. As a result, anapparatus that “comprises,” “has,” “includes” or “contains” one or moreelements possesses those one or more elements, but is not limited topossessing only those elements. Likewise, a method that “comprises,”“has,” “includes” or “contains” one or more steps possesses those one ormore steps, but is not limited to possessing only those one or moresteps.

Any embodiment of any of the disclosed methods or compositions canconsist of or consist essentially of—rather thancomprise/include/contain/have—any of the described steps, elements,and/or features. Thus, in any of the claims, the term “consisting of” or“consisting essentially of” can be substituted for any of the open-endedlinking verbs recited above, in order to change the scope of a givenclaim from what it would otherwise be using the open-ended linking verb.

The feature or features of one embodiment may be applied to otherembodiments, even though not described or illustrated, unless expresslyprohibited by this disclosure or the nature of the embodiments.

Any embodiment of any of the disclosed compounds or methods can consistof or consist essentially of—rather thancomprise/include/contain/have—any of the described steps, elements,and/or features. Thus, in any of the claims, the term “consisting of” or“consisting essentially of” can be substituted for any of the open-endedlinking verbs recited above, in order to change the scope of a givenclaim from what it would otherwise be using the open-ended linking verb.

For the purposes of the present disclosure the terms “sublingual” and“buccal” are used interchangeably. The definition of “sublingual” isadministration of a drug under the tongue to be absorbed by the tissuetherein. The definition of “buccal” is to administer a drug by placingit between your cheek and gum. For the purposes to the presentdisclosure the user can either place the disclosed compositions underthe tongue of between the check and gum, whichever mode of delivery ismore convenient. Therefore, the disclose compositions can be absorbed inany manner chosen by the user.

The feature or features of one embodiment may be applied to otherembodiments, even though not described or illustrated, unless expresslyprohibited by this disclosure or the nature of the embodiments.

A smokeless oral nicotine product can be provided to the user in aportioned or a non-portioned format. Portioned smokeless oral nicotineproducts can reduce or eliminate the handling of the tobacco by theuser, which can offer significant advantages in terms of better hygiene,convenience and/or ease of use.

Disclosed herein are compositions for sublingual delivery of nicotine.Unlike orally delivered compositions, sublingual compositions areabsorbed in the mucosa of the mouth and therefore avoid the side effectof direct contact of nicotine with the stomach, intestines and otherdigestive organs.

Disclosed herein are base compositions for sublingual or buccal deliveryof nicotine, comprising:

-   -   a) from about 0.25% to about 6% by weight of nicotine, a        nicotine salt, nicotine in combination with a resin, or mixtures        thereof;    -   b) from about 1% to about 20% by weight of an edible oil;    -   c) from about 5% to about 20% by weight of sodium bicarbonate;        and    -   d) the balance one or more carriers.

One aspect of the disclosed compositions, comprises:

-   -   a) from about 1% to about 6% by weight of nicotine, a nicotine        salt, or mixtures thereof;    -   b) from about 3% to about 20% by weight of an edible oil;    -   c) from about 10% to about 20% by weight of sodium bicarbonate;        and    -   d) the balance one or more carriers.

In one non-limiting embodiment of this aspect the base compositions,comprise:

-   -   a) from about 1% to about 3.5% by weight of nicotine, a nicotine        salt, or mixtures thereof;    -   b) from about 3% to about 10.5% by weight of an edible oil;    -   c) from about 10% to about 20% by weight of sodium bicarbonate;        and    -   d) the balance an admixture of microcrystalline cellulose and        inulin.

The disclosed base compositions can comprise from about 0.25% to about6% by weight of nicotine, a nicotine salt or nicotine in combinationwith a resin. In one embodiment, the base composition can comprise fromabout 1% to about 5% by weight of nicotine, a nicotine salt or nicotinein combination with a resin. In another embodiment, the base compositioncan comprise from about 2% to about 6% by weight of nicotine, a nicotinesalt or nicotine in combination with a resin. In a further embodiment,the base composition can comprise from about 2% to about 5% by weight ofnicotine, a nicotine salt or nicotine in combination with a resin. In ayet further embodiment, the base composition can comprise from about 3%to about 5% by weight of nicotine, a nicotine salt or nicotine incombination with a resin. In a still yet further embodiment, the basecomposition can comprise from about 0.5% to about 4% by weight ofnicotine, a nicotine salt or nicotine in combination with a resin. In ayet still another further embodiment, the base composition can comprisefrom about 0.75% to about 3% by weight of nicotine, a nicotine salt ornicotine in combination with a resin.

For example, the amount of nicotine, a nicotine salt or nicotine incombination with a resin can be 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%,0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%,4%, 5%, or 6% by weight or any fractional amounts, for example, 1.5%,3.25%, and 5.75%.

The disclosed base compositions can comprise from about 1% to about 20%by weight of an edible oil. In one embodiment the base compositions cancomprise from about 3% to about 15% by weight of an edible oil. Inanother embodiment the base compositions can comprise from about 5% toabout 17% by weight of an edible oil. In a further embodiment the basecompositions can comprise from about 7.5% to about 15% by weight of anedible oil. In a still further embodiment the base compositions cancomprise from about 5% to about 10% by weight of an edible oil. Forexample, the amount of an edible oil can be 1%, 2%, 3%, 4%, 5%, 6%, 7%,8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% byweight of an edible oil or any fractional amounts, for example, 10.5%,13.6%, and 17.5%.

According to this aspect the ratio of nicotine, a nicotine salt ornicotine in combination with a resin to an edible oil is from about 1:1to about 1:4. For example, the ratio of nicotine, a nicotine salt ornicotine in combination with a resin to an edible oil can be 1:1, 1:1.1,1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1,1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1,1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1.3.7, 1:3.8, 1:3.9, or 1:4.

The disclosed base compositions can comprise from about 5% to about 20%by weight of sodium bicarbonate. In one embodiment the base compositionscan comprise from about 5% to about 15% by weight of sodium bicarbonate.In another embodiment the base compositions can comprise from about 10%to about 20% by weight of sodium bicarbonate. In a further embodimentthe base compositions can comprise from about 12.5% to about 17.5% byweight of sodium bicarbonate. In a still further embodiment the basecompositions can comprise from about 7% to about 15% by weight of sodiumbicarbonate. For example, the amount of sodium bicarbonate can be 5%,6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%by weight of sodium bicarbonate or any fractional amounts, for example,10.5%, 13.6%, and 17.5%.

In another aspect the base compositions can comprise:

-   -   a) from about 0.5 mg to about 50 mg by weight of nicotine, a        nicotine salt, nicotine in combination with a resin, or mixtures        thereof;    -   b) from about 10 mg to about 160 mg by weight of an edible oil;        and    -   c) from about 25 mg to about 300 mg by weight of sodium        bicarbonate.

The disclosed base compositions can comprise from 0.5 mg to about 50 mgby weight of nicotine, a nicotine salt, nicotine in combination with aresin, or mixtures thereof. In one embodiment the base compositions cancomprise from 1 mg to about 50 mg by weight of nicotine, a nicotinesalt, nicotine in combination with a resin, or mixtures thereof. Inanother embodiment the base compositions can comprise from 10 mg toabout 40 mg by weight of nicotine, a nicotine salt, nicotine incombination with a resin, or mixtures thereof. In a further embodimentthe base compositions can comprise from 10 mg to about 30 mg by weightof nicotine, a nicotine salt, nicotine in combination with a resin, ormixtures thereof. In a still further embodiment the base compositionscan comprise from 15 mg to about 30 mg by weight of nicotine, a nicotinesalt, nicotine in combination with a resin, or mixtures thereof. In ayet further embodiment the base compositions can comprise from 10 mg toabout 25 mg by weight of nicotine, a nicotine salt, nicotine incombination with a resin, or mixtures thereof. The base compositions cancomprise, for example, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg,17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47mg, 48 mg, 49 mg, or 50 mg by weight of nicotine, a nicotine salt,nicotine in combination with a resin, or mixtures thereof or anyfractional amount, for example, 7.5 mg, 22.5 mg, and 34.6 mg.

The disclosed base compositions can comprise from about 10 mg to about160 mg by weight of an edible oil. In one embodiment the basecompositions can comprise from about 15 mg to about 160 mg by weight ofan edible oil. In another embodiment the base compositions can comprisefrom about 25 mg to about 120 mg by weight of an edible oil. In afurther embodiment the base compositions can comprise from about 40 mgto about 100 mg by weight of an edible oil. In a still furtherembodiment the base compositions can comprise from about 50 mg to about150 mg by weight of an edible oil. In a yet further embodiment the basecompositions can comprise from about 75 mg to about 120 mg by weight ofan edible oil. The disclosed base compositions can comprise, forexample, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg,19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89mg, 90 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98mg, 99 mg, 100 mg, 101 mg, 102, mg, 103, mg, 104 mg, 105 mg, 106 mg, 107mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg 31 mg, 132 mg, 133 mg, 134mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, or 160 mg byweight of an edible oil or any fractional amount, for example, 27.5 mg,82.5 mg, and 134.6 mg.

The disclosed base compositions can comprise from about 10 mg to about300 mg by weight of sodium bicarbonate. In one embodiment the basecompositions comprise from about 25 mg to about 100 mg by weight ofsodium bicarbonate. In another embodiment the base compositions comprisefrom about 50 mg to about 100 mg by weight of sodium bicarbonate. In afurther embodiment the base compositions comprise from about 100 mg toabout 200 mg by weight of sodium bicarbonate. In still furtherembodiment the base compositions comprise from about 150 mg to about 200mg by weight of sodium bicarbonate. In still yet further embodiment thebase compositions comprise from about 75 mg to about 100 mg by weight ofsodium bicarbonate. In a yet further embodiment the base compositionscomprise from about 150 mg to about 300 mg by weight of sodiumbicarbonate. In a yet another embodiment the base compositions comprisefrom about 225 mg to about 300 mg by weight of sodium bicarbonate. Thedisclosed base composition can comprise, for example, 10 mg, 11 mg, 12mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 90 mg, 91mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101mg, 102 mg, 103, mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128mg, 129 mg, 130 mg 31 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173mg, 174 mg, 175 mg, 167 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218mg, 219 mg, 220 mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226 mg, 227mg, 228 mg, 229 mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253 mg, 254mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, 260 mg, 261 mg, 2 62 mg, 263mg, 264 mg, 265 mg, 266 mg, 267 mg, 268 mg, 269 mg, 270 mg, 271 mg, 272mg, 273 mg, 274 mg, 275 mg, 276 mg, 277 mg, 278 mg, 279 mg, 280 mg, 281mg, 282 mg, 283 mg, 284 mg, 285 mg, 286 mg, 287 mg, 288 mg, 289 mg, 290mg, 290 mg, 291 mg, 292 mg, 293 mg, 294 mg, 295 mg, 296 mg, 297 mg, 298mg, 299 mg, or 300 mg by weight of sodium bicarbonate, or any fractionalamount, for example, 110.5, 220.7 and 250.8.

Nicotine Compounds

Disclosed herein are two sources of nicotine: naturally derived andsynthetic. The two forms of nicotine are not combined or otherwiseadmixed with one another in any of the compositions disclosed herein.The disclosed salts can be formed from either the naturally derived orthe synthetic nicotine. The word “nicotine” is used herein to refer toboth naturally derived or synthetic nicotine unless otherwise designatedas naturally occurring or synthetic nicotine.

The disclosed nicotine compounds are chosen from nicotine,pharmacologically acceptable salts of nicotine, a nicotine complexes,and polymer resins of containing nicotine. Non-limiting examples ofnicotine salts includes nicotine benzoate, nicotine lactate, nicotinemalate, nicotine ditartrate, nicotine salicylate, nicotine citrate andnicotine levulinate. Non-limiting examples of nicotine in combinationwith a resin includes nicotine polacrilex and nicotine resinate.

In one non-limiting example the nicotine salt is nicotine benzoate. Inanother non-limiting example the nicotine salt is nicotine lactate. In afurther non-limiting example the nicotine salt is nicotine malate. In ayet further non-limiting example the nicotine salt is nicotineditartrate. In a still yet further non-limiting example the nicotinesalt is nicotine salicylate. In a yet another non-limiting example thenicotine salt is nicotine citrate. In a still yet another non-limitingexample the nicotine salt is nicotine levulinate.

Nicotine can be synthesized by the procedure outlined herein below inScheme I. Synthetic details can be found in Del Castillo E et al.,“Enantioselective Synthesis of Nicotine via an Iodine-MediatedHoffmann-Loffler Reaction,” Org. Lett. 2019, 21, 705-708.

Edible Oils

The disclosed edible oils include oils that are primarilytriglyceride-containing oils. Ono-limiting examples of these oils arechosen from sunflower oil, coconut oil, canola oil, palm oil, soybeanoil, corn oil, safflower oil, and peanut oil. In one non-limitingexample the edible oil is sunflower oil. In a further non-limitingexample the edible oil is coconut oil. In a still further non-limitingexample the edible oil is canola oil. In a yet further non-limitingexample the edible oil is palm oil. In a still yet non-limiting examplethe edible oil is soybean oil. In another non-limiting example theedible oil is corn oil. In a still another non-limiting example theedible oil is safflower oil. In a yet another non-limiting example theedible oil is peanut oil.

Formulating Oils

In addition to the disclosed edible oils, formulating oils can be usedto deliver the disclosed base compositions. Formulating oils are mono-and di-glycerides of either edible oils or are synthetically preparedformulating oils prepared by reacting glycerin with a stoichiometricamount of a fatty acid to provide a formulating oil which is not acomplete triglyceride. Non-limiting examples of formulating oils arechosen from glyceryl monocaprylate, glyceryl dibehenate, glycerylmonooleate, glyceryl dioleate, glyceryl monocaprylate, glyceryldicaprylate, glyceryl monomyristate, and glyceryl dimyristate.

Carriers

In one aspect the disclosed carriers are polysaccharides. Non-limitingexamples of poly saccharide carriers include inulin, galactogen,cellulose, chitin, pectin, psyllium, guar, hemicellulose, potato starch,and partially hydrolyzed polysaccharides. In another aspect the carriersare sugar alcohols, for example, sorbitol, erythritol, xylitol,lactitol, maltitol, mannitol, hydrogenated starch hydrolysates,isomaltose, or any combination thereof. In a further aspect carriercomponent is based on a native or chemically modified agar, alginates,carrageenan gum, cellulose, chitosan, chitin, cyclodextrin, dextran,gellan gum, glycogen, glycosaminoglycan, gum karaya, inulin, pectin,polydextrose, xanthan gum, or any other starches, gums or otherpolysaccharide, including functionalized derivatives, dextrinized,hydrolyzed, oxidized, alkylated, hydroxyalkylated, acetylated,fractionated, and physically modified starches and mixtures thereof. Insome embodiments glycerin and/or propylene glycol can be added as acarrier.

In one aspect the carrier can serve as a bulking agent. In oneembodiment, microcrystalline cellulose is utilized as a carrier in thebase compositions and as a bulking agent in the pouches disclosed hereinbelow. In another embodiment, two or more carriers can be combined, forexample, microcrystalline cellulose and inulin. This combination can beutilized in both the base composition, as well as in the pouches. As itrelates to the disclosed pouches, dextrin is added as a bulking agent,however, dextrin can also serve as carrier for any flavors that theformulator wishes to add. For example, ethylvanillin is a compound whichprovides vanilla flavoring. Ethylvanillin can be compounded withdextrin, microcrystalline cellulose or inulin and then admixed with thebulking agents or other carriers.

In one aspect of the one or more carriers, one of the carriers is watersoluble while others are not. This allows the formulator to control therelease of the active base when the active base is delivered by way of anon-water soluble, but water permeable pouch as described herein below.This combining of carriers allows the delivery of nicotine either via anicotine salt or by way of a polymer supported nicotine, for example,polacrilex.

The disclosed compositions can comprise from about 80% to about 95% byweight of one or more carriers. In one embodiment the disclosedcompositions can comprise from about 80% to about 90% by weight of oneor more carriers. In another embodiment the disclosed compositions cancomprise from about 85% to about 95% by weight of one or more carriers.In a further embodiment the disclosed compositions can comprise fromabout 85% to about 90% by weight of one or more carriers.

Antioxidants

The disclosed compositions can comprise about 0.05% or less of anantioxidant. Non-limiting examples of an antioxidant includes butylatedhydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate(PG), tert-butyl hydroquinone (TBHQ), and mixtures thereof.

The following tables disclose non-limiting examples of the base nicotinedelivery compositions.

TABLE 1 Ingredients (mg) 1 2 3 4 5 Nicotine benzoate 5 17.5 7.5 15 17.5Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 430 660 370 340 347.5 Total 500 500 500 500 500

TABLE 2 Ingredients (mg) 6 7 8 9 10 Nicotine benzoate 12.5 17.5 5 10 7.5Sunflower oil 25 52.5 15 30 22.5 Sodium bicarbonate 75 75 100 100 100Inulin LV 110 387.5 355 380 360 340 Total 500 500 500 500 500

TABLE 3 Ingredients (mg) 11 12 13 14 15 Nicotine benzoate 5 17.5 7.5 1517.5 Sunflower oil 20 70 30 60 70 Sodium bicarbonate 50 90 100 100 100Inulin LV 110 425 322.5 362.5 325 330 Total 500 500 500 500 500

TABLE 4 Ingredients (mg) 16 17 18 19 20 Nicotine benzoate 5 17.5 7.5 1517.5 coconut oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100100 Inulin LV 110 430 660 370 340 347.5 Total 500 500 500 500 500

TABLE 5 Ingredients (mg) 21 22 23 24 25 Nicotine benzoate 12.5 17.5 5 107.5 coconut oil 25 52.5 15 30 22.5 Sodium bicarbonate 75 75 100 100 100Inulin LV 110 387.5 355 380 360 340 Total 500 500 500 500 500

TABLE 6 Ingredients (mg) 26 27 28 29 30 Nicotine benzoate 5 17.5 7.5 1517.5 coconut oil 20 70 30 60 70 Sodium bicarbonate 50 90 100 100 100Inulin LV 110 425 322.5 362.5 325 330 Total 500 500 500 500 500

TABLE 7 Ingredients (mg) 31 32 33 34 35 Nicotine benzoate 5 17.5 7.5 1517.5 soybean oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100100 Inulin LV 110 430 660 370 340 347.5 Total 500 500 500 500 500

TABLE 8 Ingredients (mg) 36 37 38 39 40 Nicotine benzoate 5 17.5 7.5 1517.5 canola oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 430 660 370 340 347.5 Total 500 500 500 500 500

TABLE 9 Ingredients (mg) 41 42 43 44 45 Nicotine benzoate 5 17.5 7.5 1517.5 palm oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 430 660 370 340 347.5 Total 500 500 500 500 500

TABLE 10 Ingredients (mg) 46 47 48 49 50 Nicotine benzoate 12.5 17.5 510 7.5 Sunflower oil 43.75 61.25 17.5 35 26.25 Sodium bicarbonate 150125 125 150 125 Inulin LV 110 543.75 546.25 602.5 455 591.25 Total 750750 750 750 750

TABLE 11 Ingredients (mg) 51 52 53 54 55 Nicotine benzoate 10 35 15 3035 Sunflower oil 30 105 45 90 70 Sodium bicarbonate 100 200 200 200 200Inulin LV 110 860 660 740 680 695 Total 1000 1000 1000 1000 1000

TABLE 12 Ingredients (mg) 56 57 58 59 60 Nicotine benzoate 25 35 10 2015 Sunflower oil 50 105 30 60 45 Sodium bicarbonate 150 150 200 200 200Inulin LV 110 775 710 760 720 740 Total 1000 1000 1000 1000 1000

TABLE 13 Ingredients (mg) 61 62 63 64 65 Nicotine benzoate 10 35 15 3035 Sunflower oil 40 140 60 120 140 Sodium bicarbonate 100 200 200 200200 Inulin LV 110 850 625 725 650 625 Total 1000 1000 1000 1000 1000

TABLE 14 Ingredients (mg) 66 67 68 69 70 Nicotine benzoate 10 35 15 3035 coconut oil 30 105 45 90 70 Sodium bicarbonate 100 200 200 200 200Inulin LV 110 860 660 740 680 695 Total 1000 1000 1000 1000 1000

TABLE 15 Ingredients (mg) 71 72 73 74 75 Nicotine benzoate 25 35 10 2015 coconut oil 50 105 30 60 45 Sodium bicarbonate 150 150 200 200 200Inulin LV 110 775 710 760 720 740 Total 1000 1000 1000 1000 1000

TABLE 16 Ingredients (mg) 76 77 78 79 80 Nicotine benzoate 10 35 15 3035 coconut oil 40 140 60 120 140 Sodium bicarbonate 100 200 200 200 200Inulin LV 110 850 625 725 650 625 Total 1000 1000 1000 1000 1000

TABLE 17 Ingredients (mg) 81 82 83 84 85 Nicotine benzoate 25 35 10 2015 coconut oil 100 140 40 80 60 Sodium bicarbonate 150 150 200 200 200Inulin LV 110 725 675 750 700 725 Total 1000 1000 1000 1000 1000

TABLE 18 Ingredients (mg) 86 87 88 89 90 Nicotine benzoate 10 35 15 3035 soybean oil 30 105 45 90 70 Sodium bicarbonate 100 200 200 200 200Inulin LV 110 860 660 740 680 695 Total 1000 1000 1000 1000 1000

TABLE 19 Ingredients (mg) 91 92 93 94 95 Nicotine benzoate 25 35 10 2015 soybean oil 50 105 30 60 45 Sodium bicarbonate 150 150 200 200 200Inulin LV 110 775 710 760 720 740 Total 1000 1000 1000 1000 1000

TABLE 20 Ingredients (mg) 96 97 98 99 100 Nicotine benzoate 10 35 15 3035 soybean oil 40 140 60 120 140 Sodium bicarbonate 100 200 200 200 200Inulin LV 110 850 625 725 650 625 Total 1000 1000 1000 1000 1000

TABLE 21 Ingredients (mg) 101 102 103 104 105 Nicotine benzoate 10 35 1530 35 canola oil 30 105 45 90 70 Sodium bicarbonate 100 200 200 200 200Inulin LV 110 860 660 740 680 695 Total 1000 1000 1000 1000 1000

TABLE 22 Ingredients (mg) 106 107 108 109 110 Nicotine benzoate 25 35 1020 15 canola oil 50 105 30 60 45 Sodium bicarbonate 150 150 200 200 200Inulin LV 110 775 710 760 720 740 Total 1000 1000 1000 1000 1000

TABLE 23 Ingredients (mg) 111 112 113 114 115 Nicotine benzoate 10 35 1530 35 canola oil 40 140 60 120 140 Sodium bicarbonate 100 200 200 200200 Inulin LV 110 850 625 725 650 625 Total 1000 1000 1000 1000 1000

TABLE 24 Ingredients (mg) 116 117 118 119 120 Nicotine benzoate 15 52.522.5 45 52.5 Sunflower oil 45 157.5 67.5 135 105 Sodium bicarbonate 150300 300 300 300 Inulin LV 110 1290 990 1110 1020 1042.5 Total 1500 15001500 1500 1500

TABLE 25 Ingredients (mg) 121 122 123 124 125 Nicotine benzoate 37.552.5 15 30 22.5 Sunflower oil 75 157.5 45 90 67.5 Sodium bicarbonate 225225 300 300 300 Inulin LV 110 1162.5 1065 1140 1080 1110 Total 1500 15001500 1500 1500

TABLE 26 Ingredients (mg) 126 127 128 129 130 Nicotine benzoate 15 52.522.5 45 30 Sunflower oil 60 210 90 180 120 Sodium bicarbonate 150 300300 250 300 Inulin LV 110 1275 937.5 1087 1025 1050 Total 1500 1500 15001500 1500

TABLE 27 Ingredients (mg) 131 132 133 134 135 Nicotine benzoate 37.5 5015 30 20 Sunflower oil 150 200 60 1200 80 Sodium bicarbonate 225 225 300300 300 Inulin LV 110 1087.5 1025 1125 1050 110 Total 1500 1500 15001500 1500

TABLE 28 Ingredients (mg) 136 137 138 139 140 Nicotine polacrilex 5 17.57.5 15 17.5 Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100100 100 100 Inulin LV 110 430 660 370 340 347.5 Total 500 500 500 500500

TABLE 29 Ingredients (mg) 141 142 143 144 145 Nicotine polacrilex 12.517.5 5 10 7.5 Sunflower oil 25 52.5 15 30 22.5 Sodium bicarbonate 75 75100 100 100 Inulin LV 110 387.5 355 380 360 340 Total 500 500 500 500500

TABLE 30 Ingredients (mg) 146 147 148 149 150 Nicotine polacrilex 5 17.57.5 15 17.5 Sunflower oil 20 70 30 60 70 Sodium bicarbonate 50 90 100100 100 Inulin LV 110 425 322.5 362.5 325 330 Total 500 500 500 500 500

TABLE 31 Ingredients (mg) 151 152 153 154 155 Nicotine polacrilex 5 17.57.5 15 17.5 coconut oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100100 100 Inulin LV 110 430 660 370 340 347.5 Total 500 500 500 500 500

TABLE 32 Ingredients (mg) 156 157 158 159 160 Nicotine polacrilex 12.517.5 5 10 7.5 Coconut oil 25 52.5 15 30 22.5 Sodium bicarbonate 75 75100 100 100 Inulin LV 110 387.5 355 380 360 340 Total 500 500 500 500500

TABLE 33 Ingredients (mg) 161 162 163 164 165 Nicotine polacrilex 5 17.57.5 15 17.5 coconut oil 20 70 30 60 70 Sodium bicarbonate 50 90 100 100100 Inulin LV 110 425 322.5 362.5 325 330 Total 500 500 500 500 500

TABLE 34 Ingredients (mg) 166 167 168 169 170 Nicotine polacrilex 5 17.57.5 15 17.5 soybean oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100100 100 Inulin LV 110 430 660 370 340 347.5 Total 500 500 500 500 500

TABLE 35 Ingredients (mg) 171 172 173 174 175 Nicotine polacrilex 12.517.5 5 10 7.5 Soybean oil 25 52.5 15 30 22.5 Sodium bicarbonate 75 75100 100 100 Inulin LV 110 387.5 355 380 360 340 Total 500 500 500 500500

TABLE 36 Ingredients (mg) 176 177 178 179 180 Nicotine polacrilex 5 17.57.5 15 17.5 Soybean oil 20 70 30 60 70 Sodium bicarbonate 50 90 100 100100 Inulin LV 110 425 322.5 362.5 325 330 Total 500 500 500 500 500

TABLE 37 Ingredients (mg) 181 182 183 184 185 Nicotine polacrilex 5 17.57.5 15 17.5 canola oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100100 100 Inulin LV 110 430 660 370 340 347.5 Total 500 500 500 500 500

TABLE 38 Ingredients (mg) 186 187 188 189 190 Nicotine polacrilex 12.517.5 5 10 7.5 canola oil 25 52.5 15 30 22.5 Sodium bicarbonate 75 75 100100 100 Inulin LV 110 387.5 355 380 360 340 Total 500 500 500 500 500

TABLE 39 Ingredients (mg) 191 192 193 194 195 Nicotine polacrilex 5 17.57.5 15 17.5 canola oil 20 70 30 60 70 Sodium bicarbonate 50 90 100 100100 Inulin LV 110 425 322.5 362.5 325 330 Total 500 500 500 500 500

TABLE 40 Ingredients (mg) 196 197 198 199 200 Nicotine polacrilex 12.517.5 5 10 7.5 Sunflower oil 43.75 61.25 17.5 35 26.25 Sodium bicarbonate150 125 125 150 125 Inulin LV 110 543.75 546.25 602.5 455 591.25 Total750 750 750 750 750

TABLE 41 Ingredients (mg) 201 202 203 204 205 Nicotine polacrilex 10 3515 30 35 Sunflower oil 40 140 60 120 140 Sodium bicarbonate 100 200 200200 200 Inulin LV 110 850 625 725 650 625 Total 1000 1000 1000 1000 1000

TABLE 42 Ingredients (mg) 206 207 208 209 210 Nicotine polacrilex 25 3510 20 15 Sunflower oil 100 140 40 80 60 Sodium bicarbonate 150 150 200200 200 Inulin LV 110 725 675 750 700 725 Total 1000 1000 1000 1000 1000

TABLE 43 Ingredients (mg) 211 212 213 214 215 Nicotine polacrilex 10 3515 30 35 Sunflower oil 30 105 45 90 70 Sodium bicarbonate 100 200 200200 200 Inulin LV 110 860 660 740 680 695 Total 1000 1000 1000 1000 1000

TABLE 44 Ingredients (mg) 216 217 218 219 220 Nicotine polacrilex 25 3510 20 15 Sunflower oil 50 105 30 60 45 Sodium bicarbonate 150 150 200200 200 Inulin LV 110 775 710 760 720 740 Total 1000 1000 1000 1000 1000

TABLE 45 Ingredients (mg) 221 222 223 224 225 Nicotine polacrilex 1552.5 22.5 45 52.5 Sunflower oil 45 157.5 67.5 135 105 Sodium bicarbonate150 300 300 300 300 Inulin LV 110 1290 990 1110 1020 1042.5 Total 15001500 1500 1500 1500

TABLE 46 Ingredients (mg) 226 227 228 229 230 Nicotine polacrilex 37.552.5 15 30 22.5 Sunflower oil 75 157.5 45 90 67.5 Sodium bicarbonate 225225 300 300 300 Inulin LV 110 1162.5 1065 1140 1080 1110 Total 1500 15001500 1500 1500

TABLE 47 Ingredients (mg) 231 232 233 234 235 Nicotine polacrilex 1552.5 22.5 45 30 Sunflower oil 60 210 90 180 120 Sodium bicarbonate 150300 300 250 300 Inulin LV 110 1275 937.5 1087 1025 1050 Total 1500 15001500 1500 1500

TABLE 48 Ingredients (mg) 236 237 238 239 240 Nicotine polacrilex 37.550 15 30 20 Sunflower oil 150 200 60 1200 80 Sodium bicarbonate 225 225300 300 300 Inulin LV 110 1087.5 1025 1125 1050 110 Total 1500 1500 15001500 1500

TABLE 49 Ingredients (mg) 241 242 243 244 245 Nicotine polacrilex 10 3515 30 35 coconut oil 40 140 60 120 140 Sodium bicarbonate 100 200 200200 200 Inulin LV 110 850 625 725 650 625 Total 1000 1000 1000 1000 1000

TABLE 50 Ingredients (mg) 246 247 248 249 250 Nicotine polacrilex 25 3510 20 15 coconut oil 100 140 40 80 60 Sodium bicarbonate 150 150 200 200200 Inulin LV 110 725 675 750 700 725 Total 1000 1000 1000 1000 1000

TABLE 51 Ingredients (mg) 251 252 253 254 255 Nicotine polacrilex 10 3515 30 35 coconut oil 30 105 45 90 70 Sodium bicarbonate 100 200 200 200200 Inulin LV 110 860 660 740 680 695 Total 1000 1000 1000 1000 1000

TABLE 51 Ingredients (mg) 256 257 258 259 260 Nicotine polacrilex 25 3510 20 15 coconut oil 50 105 30 60 45 Sodium bicarbonate 150 150 200 200200 Inulin LV 110 775 710 760 720 740 Total 1000 1000 1000 1000 1000

TABLE 52 Ingredients (mg) 261 262 263 264 265 Nicotine polacrilex 10 3515 30 35 soybean oil 40 140 60 120 140 Sodium bicarbonate 100 200 200200 200 Inulin LV 110 850 625 725 650 625 Total 1000 1000 1000 1000 1000

TABLE 53 Ingredients (mg) 266 267 268 269 270 Nicotine polacrilex 25 3510 20 15 soybean oil 100 140 40 80 60 Sodium bicarbonate 150 150 200 200200 Inulin LV 110 725 675 750 700 725 Total 1000 1000 1000 1000 1000

TABLE 54 Ingredients (mg) 271 272 273 274 275 Nicotine polacrilex 10 3515 30 35 soybean oil 30 105 45 90 70 Sodium bicarbonate 100 200 200 200200 Inulin LV 110 860 660 740 680 695 Total 1000 1000 1000 1000 1000

TABLE 55 Ingredients (mg) 276 277 278 279 280 Nicotine polacrilex 25 3510 20 15 soybean oil 50 105 30 60 45 Sodium bicarbonate 150 150 200 200200 Inulin LV 110 775 710 760 720 740 Total 1000 1000 1000 1000 1000

Kits

Disclosed herein are kits for sublingual delivery of nicotine. The kitscontain a base nicotine delivery system which comprises the activeingredients and a non-water soluble liquid permeable pouch into whichthe active ingredients and any necessary adjunct ingredients useful fordelivery of the nicotine, nicotine salt of nicotine resin compositions.In one aspect the kit comprises a pouch containing a disclosedcomposition, comprising:

-   -   A) a liquid permeable pouch comprising a non-nicotine        composition comprising:        -   a) one or more delivery agents; and        -   b) a bulking agent; and    -   B) a base nicotine delivery composition comprising:        -   a) nicotine, a nicotine salt, nicotine in combination with a            resin, or mixtures thereof;        -   b) sunflower oil;        -   c) sodium bicarbonate; and        -   d) the balance one or more carriers.

Delivery Control Agents

In order to control sublingual delivery of the disclosednicotine-containing compositions the kits contain one or more agentsthat control the release of nicotine into the mouth of the use. Theseagents are typically formulated after assembly of the base nicotinedelivery compositions; however, the formulator can add a deliverycontrol agent as part of a carrier system.

In one embodiment the delivery agents are solubilizers, for example,lecithins, polyoxyethylene stearate, polyoxyethylene sorbitan fatty acidesters, fatty acid salts, mono and diacetyl tartaric acid esters of monoand diglycerides of edible fatty acids, citric acid esters of mono anddiglycerides of edible fatty acids, saccharose esters of fatty acids,polyglycerol esters of fatty acids, polyglycerol esters ofinteresterified castor oil acid (E476), sodium stearoyl lactylate,sodium lauryl sulfate and sorbitan esters of fatty acids andpolyoxyethylated hydrogenated castor oil (for example, CREMOPHOR™),block copolymers of ethylene oxide and propylene oxide (for example, oneor more PLURONICS™ or POLOXAMERS™), polyoxyethylene fatty alcoholethers, polyoxyethylene sorbitan fatty acid esters, sorbitan esters offatty acids and polyoxyethylene stearic acid esters.

In one embodiment the delivery agent is chosen from sodium stearoyllactylate, sodium lauryl sulfate, glycerol, propylene glycol,b-cyclodextrin and propylene glycol 400 (PEG 400).

Non-limiting examples of solubilizers includes glycerol, propyleneglycol, b-cyclodextrin and propylene glycol 400 (PEG 400).

In one aspect of the disclosed kits, the kits comprise:

-   -   A) a liquid permeable pouch comprising a non-nicotine        composition comprising:        -   a) one or more delivery agents; and        -   b) a bulking agent; and    -   B) a base nicotine delivery composition comprising:        -   a) nicotine, a nicotine salt, nicotine in combination with a            resin, or mixtures thereof;        -   b) sunflower oil;        -   c) sodium bicarbonate; and        -   d) the balance one or more carriers.

In one embodiment of this aspect, the kits comprise:

-   -   A) a liquid permeable pouch comprising a non-nicotine        composition comprising:        -   a) one or more delivery agents; and        -   b) a bulking agent; and    -   B) a base nicotine delivery composition comprising:        -   a) from about 1% to about 6% by weight of nicotine, a            nicotine salt, nicotine in combination with a resin, or            mixtures thereof;        -   b) from about 3% to about 20% by weight of sunflower oil;        -   c) from about 10% to about 20% by weight of sodium            bicarbonate; and        -   d) the balance one or more carriers.

In one iteration of this embodiment, the kits comprise:

-   -   A) a liquid permeable pouch comprising a non-nicotine        composition comprising:        -   a) maltitol; and        -   b) an admixture of microcrystalline cellulose and inulin;            and    -   B) a base nicotine delivery composition comprising:        -   a) from about 1% to about 6% by weight of nicotine, a            nicotine salt, nicotine in combination with a resin, or            mixtures thereof;        -   b) from about 3% to about 20% by weight of sunflower oil;        -   c) from about 10% to about 20% by weight of sodium            bicarbonate; and        -   d) the balance:            -   i) dextrose; and            -   ii) a flavorant.

In a further aspect of the disclosed kits, the kits comprise:

-   -   A) a liquid permeable pouch comprising a non-nicotine        composition comprising:        -   a) one or more delivery agents; and        -   b) a bulking agent;        -   c) optionally one or more formulating oils; and    -   B) a base nicotine delivery composition comprising:        -   a) nicotine, a nicotine salt, nicotine in combination with a            resin, or mixtures thereof;        -   b) sunflower oil;        -   c) sodium bicarbonate;        -   d) one or more formulating oils; and        -   e) the balance one or more carriers.

In one embodiment of this aspect, the kits comprise:

-   -   A) a liquid permeable pouch comprising a non-nicotine        composition comprising:        -   a) one or more delivery agents; and        -   b) a bulking agent; and    -   B) a base nicotine delivery composition comprising:        -   a) from about 1% to about 6% by weight of nicotine, a            nicotine salt, nicotine in combination with a resin, or            mixtures thereof;        -   b) from about 3% to about 20% by weight of sunflower oil;        -   c) from about 10% to about 20% by weight of sodium            bicarbonate;        -   d) from about 0.5% to about 1% by weight of a formulating            oil; and        -   d) the balance one or more carriers.

Non-limiting examples of flavorants include apple, banana, cherry,cinnamon, grape, orange, pear, pineapple, raspberry, blueberry,strawberry, spearmint, peppermint, wintergreen, and vanilla.

Disclosed herein is a kit, comprising:

-   -   A) a liquid permeable pouch comprising a non-nicotine        composition comprising:        -   a) one or more delivery control agents; and        -   b) a bulking agent; and    -   B) a base nicotine delivery composition comprising:        -   a) nicotine, a nicotine salt, nicotine in combination with a            resin, or mixtures thereof;        -   b) sunflower oil;        -   c) sodium bicarbonate; and        -   d) the balance one or more carriers.

In one non-limiting example, the kit comprises:

-   -   A) a liquid permeable pouch comprising a non-nicotine        composition comprising:        -   a) one or more delivery control agents; and        -   b) a bulking agent; and    -   B) from about 70 mg to about 510 mg of an active base delivery        system, comprising:        -   a) from about 0.5 mg to about 50 mg by weight of nicotine, a            nicotine salt, nicotine in combination with a resin, or            mixtures thereof;        -   b) from about 10 mg to about 160 mg by weight of sunflower            oil; and        -   c) from about 25 mg to about 300 mg by weight of sodium            bicarbonate;        -   d) from about 350 mg to about 1500 mg of one or more            carriers; and        -   e) the balance one or more delivery control agents.

In another non-limiting example, the kit comprises:

-   -   A) a liquid permeable pouch comprising a non-nicotine        composition comprising:        -   a) one or more delivery control agents; and        -   b) a bulking agent; and    -   B) from about 70 mg to about 510 mg of an active base delivery        system, comprising:        -   a) from about 0.5 mg to about 50 mg by weight of nicotine, a            nicotine salt, nicotine in combination with a resin, or            mixtures thereof;        -   b) from about 10 mg to about 160 mg by weight of sunflower            oil; and        -   c) from about 25 mg to about 300 mg by weight of sodium            bicarbonate;        -   d) from about 350 mg to about 1500 mg of one or more            carriers; and        -   e) the balance one or more delivery control agents.

Preparation

The disclosed base compositions can be prepared by the following generalprocedure. Nicotine, a nicotine salt, or nicotine in combination with aresin, is combined with sunflower oil in a vessel with adequatestirring. The amount of each ingredient varies depending upon theformulator's choice of the ratio of the nicotine-containing ingredientand sunflower oil, i.e., the ratio of nicotine-containing ingredient tosunflower oil can be, as disclosed herein above, from about 1:1 to about1:3. The choice of ratio will also dictate the relative amounts ofadjunct ingredients that are added. With stirring, thenicotine-containing ingredient sunflower oil admixture is then slowlyheated to from about 50° C. to about 75° C., again predicated on theratio of ingredients and the choice of excipients.

At this point antioxidants, as well as other adjunct ingredients can beoptionally added to the nicotine-containing compound/sunflower oiladmixture during heating. The amount and ratio of any antioxidants addedto the admixture varies depending upon the formulator's choice. In onenon-limiting embodiment, the amount of antioxidant is from about 0.01%to about 0.10% by weight of the admixture.

Following the optional addition of an antioxidant and/or other adjunctingredients, the resulting admixture is then slowly added to a dryparticulate substrate with sufficient mixing to form a homogenousdispersion. The quantity of the admixture that is added to the substrateis from about 5% to about 60% by weight. The final dispersion is thendehydrated by which ever means chosen by the formulator, for example,oven drying, lyophilization, convection drying, microwave radiation,etc. In one non-limiting embodiment, the dispersion is dried from about45 to about 135 minutes. Depending upon many factors including the typeof adjunct ingredients and the ratio of the nicotine-containing compoundto sunflower oil, the time can be shortened or lengthened.

At this point and alkalizing agent is incorporated. In one non-limitingexample, sodium bicarbonate is used as the alkalizing agent. The amountof alkalizing agent is predicated on the amounts of other ingredientsand the choice of substrate. In one non-limiting embodiment thecomposition can comprise from about 1% to about 25% by weight of thealkalizing agent.

After homogenizing the alkalizing agent into the homogeneous admixturenow formed, other adjunct ingredients can be added. Non-limitingexamples include bulking agents which provide a mouthfeel that iscompatible with the pouches, thereby providing the user with a feelingof “substance” inside the pounch. Bulking agents includemicrocrystalline cellulose and inulin. In addition, sweeteners, forexample, maltitol, and/or flavoring compounds are added to providedifferent oral sensations.

The resulting composition can then be further compounded with otheradjunct ingredients, at levels that vary depending upon the formulator'schoice, such as bulking agents (e.g., microcrystalline cellulose), highpotency sweeteners (e.g., maltitol) and/or flavoring compounds, andultimately rendered in various different oral or intraoral form factors.

In one non-limiting example, nicotine benzoate (15 g) and sunflower oil(45 g) are combined in a stainless-steel reaction vessel with efficientstirring and heated to 50° C. until homogeneous. The nicotine benzoatesunflower oil admixture is then slowly metered into inulin (500 g) as adry particulate substrate compound while mixing until homogeneouslydispersed. Sodium bicarbonate (20 g) is added while mixing untilhomogenously dispersed. The admixture is then placed in a convectionairflow dehydration chamber for 90 minutes to remove remaining moistureand effect a molecular association between the nicotine and thesunflower oil infused dry particulate. The resulting composition is thencombined with microcrystalline cellulose (200 g), maltitol (175 g) andspearmint flavoring (100 g) and then charged to unit dose oral pouches.

Pouches

The properties of the pouch can influence the release of the nicotine,nicotine salt, or nicotine in combination with a resin from the pouchcomposition and thereby possibly influence the rate of uptake by theuser. The disclosed pouches comprise water insoluble fiber which allowsmoisture, typically the user's saliva, to enter the pouch and solubilizethe water-soluble components.

Disclosed herein are water-insoluble pouches which can compriseinsoluble fiber, for example, wheat fibers, oat fibers, pea fibers, ricefiber, maize fibers, oat fibers, tomato fibers, barley fibers, ryefibers, sugar beet fibers, buckwheat fibers, potato fibers, cellulosefibers, apple fibers, cocoa fibers, cellulose fiber, powdered cellulose,bamboo fibers, bran fibers or combinations thereof.

In one embodiment the disclosed pouches comprise cellulose prepared byprocessing alpha-cellulose obtained as a pulp from strains of fibrousplant materials, such as wood pulp. In a further embodiment the pouchescan comprise wheat fibers, oat fibers, or combinations thereof.

The following are non-limiting examples of plant fibers Vitacel WF 600™,Vitacel HF 600™, Vitacel P95™, Vitacel WF 200™, Vitacel LOO™, VitacelErbsenfaser EF 150™, Vitacel bamboo fiberbaf 90™, Vitacel HF 600™,Vitacel Cellulose L700G™, Vitacel PF200™, Vitacel potatofiber KF200™,Vitacel bamboo fiberhaf BAF40™, Vitacel Haferfaser/oat fiber HF-401-30™,Vitacel L 00™, Vitacel Cellulose L700G™, Vitacel LC1000™, VitacelL600-20™, Vitacel L600™ or combination thereof.

In formulating pouches containing various amounts of the base nicotinedelivery composition it is one embodiment of the present disclosure thatthe amount of water-insoluble fiber can be reduced without compromisingthe mouthfeel during use. It is important that the pouch material doesnot cause swelling in use because this fact can counteract thedissolution of the water-soluble component, thereby preventing the userfrom experiencing any decrease in pouch content during use.

In addition, the pouch composition can also provide for a desirablemouthfeel such as a soft and/or sticky texture. The desirable textureand mouthfeel can be obtained while still being able to storemanufactured pouches together in abutment, for example, in cans and thelike without sticking or clumping together to result in ruptures of thepouches when being removed. The desirable mouthfeel can in someembodiments also comprise a tingling sensation reminiscent of tobaccopouches, but without many of the undesirable effects associatedtherewith, for example, discoloring of tissue.

In one aspect of the disclosed kits, the kits comprise an active basecomposition and a pouch for delivery of nicotine sublingually to theuser.

The kits comprise a water-permeable pouch, into which an active basecomposition and a delivery system is added. The disclosed pouchescomprise:

-   -   A) from about 5% to about 20% by weight of an active base        composition, comprising”        -   a) from about 1% to about 6% by weight of nicotine, a            nicotine salt, nicotine in combination with a resin, or            mixtures thereof;        -   b) from about 3% to about 20% by weight of sunflower oil;        -   c) from about 10% to about 20% by weight of sodium            bicarbonate; and    -   B) from about 80% to about 95% by weight of a delivery system        wherein the delivery control system contains one or more        delivery control agents, carriers, solubilizers or mixtures        thereof.

In one embodiment of this aspect, the pouches comprise:

-   -   A) from about 70 mg to about 510 mg of an active base        composition, comprising:        -   a) from about 5 mg to about 50 mg by weight of nicotine            benzoate;        -   b) from about 15 mg to about 160 mg by weight of sunflower            oil;        -   c) from about 50 mg to about 300 mg by weight of sodium            bicarbonate;    -   B) from about 350 mg to about 1500 mg of one or more carriers;        and    -   C) the balance one or more delivery control agents.

In one iteration of this embodiment, the one or more carriers serves asthe delivery control agent. For example, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine        benzoate;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of a carrier        chosen from inulin, galactogen, cellulose, chitin, pectin,        psyllium, guar, hemicellulose, potato starch, or partially        hydrolyzed polysaccharides.

In another iteration of this embodiment, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine        benzoate;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of a carrier        chosen from, sorbitol, erythritol, xylitol, lactitol, maltitol,        mannitol, hydrogenated starch hydrolysates, isomaltose, or any        combination thereof.

In a still further iteration of this embodiment, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine        benzoate;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of inulin.

In a yet still further iteration of this embodiment, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine        benzoate;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of        microcrystalline cellulose.

In a yet still further iteration of this embodiment, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine benzoat;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of an admixture        of inulin and microcrystalline cellulose.

In another embodiment of this aspect, the pouches comprise:

-   -   A) from about 70 mg to about 510 mg of an active base        composition, comprising:        -   a) from about 5 mg to about 50 mg by weight of nicotine            polacrilex;        -   b) from about 15 mg to about 160 mg by weight of sunflower            oil;        -   c) from about 50 mg to about 300 mg by weight of sodium            bicarbonate;    -   B) from about 350 mg to about 1500 mg of one or more carriers;        and    -   C) the balance one or more delivery control agents.

In one iteration of this embodiment, the one or more carriers serves asthe delivery control agent. For example, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine        polacrilex;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of a carrier        chosen from inulin, galactogen, cellulose, chitin, pectin,        psyllium, guar, hemicellulose, potato starch, or partially        hydrolyzed polysaccharides.

In another iteration of this embodiment, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine        polacrilex;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of a carrier        chosen from, sorbitol, erythritol, xylitol, lactitol, maltitol,        mannitol, hydrogenated starch hydrolysates, isomaltose, or any        combination thereof.

In a still further iteration of this embodiment, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine        polacrilex;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of inulin.

In a yet still further iteration of this embodiment, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine        polacrilex;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of        microcrystalline cellulose.

In a yet still further iteration of this embodiment, a pouch comprising:

-   -   a) from about 5 mg to about 50 mg by weight of nicotine        polacrilex;    -   b) from about 15 mg to about 160 mg by weight of sunflower oil;    -   c) from about 50 mg to about 300 mg by weight of sodium        bicarbonate; and    -   d) from about 300 mg to about 1300 mg by weight of an admixture        of inulin and microcrystalline cellulose.

The disclosed compositions can comprise from about 80% to about 95% byweight of one or more delivery control agents, carriers, solubilizers ormixtures thereof. In one embodiment the disclosed compositions cancomprise from about 80% to about 90% by weight of one or more deliverycontrol agents, carriers, solubilizers or mixtures thereof. In anotherembodiment the disclosed compositions can comprise from about 85% toabout 95% by weight of one or more delivery control agents, carriers,solubilizers or mixtures thereof. In a further embodiment the disclosedcompositions can comprise from about 85% to about 90% by weight of oneor more delivery control agents, carriers, solubilizers or mixturesthereof.

Process

The disclosed base compositions can be prepared by the following generalprocedure. Nicotine, a nicotine salt, or nicotine in combination with aresin, is combined with sunflower oil in a vessel with adequatestirring. The amount of each ingredient varies depending upon theformulator's choice of the ratio of the nicotine-containing ingredientand sunflower oil, i.e., the ratio of nicotine-containing ingredient tosunflower oil is from about 1:1 to about 1:3. The choice of ratio willalso dictate the relative amounts of adjunct ingredients that are added.With stirring, the nicotine-containing ingredient sunflower oiladmixture is then slowly heated to from about 50° C. to about 75° C.,again predicated on the ratio of ingredients and the choice ofexcipients.

In one non-limiting example, nicotine benzoate (15 g) and sunflower oil(45 g) are combined in a stainless-steel reaction vessel with efficientstirring and heated to 50° C. until homogeneous. Inulin (500 g) isslowly metered in and stirring continued until all the inulin isdispersed. Sodium bicarbonate (150 g) is slowly added while raising thetemperature to 60° C. Once the admixture is homogeneous, inulin (790 g)is added at a rate to maintain a homogeneous admixture. The admixture isthen slowly cooled to 30° C. and placed in a vacuum oven for 5 hours toremove all of the remaining moisture. The resulting composition can thenbe combined with additional inulin or microcrystalline cellulose thencharged to one or more pouches.

The following are non-limiting examples of compositions delivered by wayof an insoluble plant or synthetic pouch.

Example 1

Ingredients (mg) A B C D E Nicotine benzoate 5 17.5 7.5 15 17.5Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 300 460 170 240 147.5 β-cyclodextrin 130 200 200 100 200Total 500 500 500 500 500

Example 2

Ingredients (mg) F G H I J Nicotine benzoate 5 17.5 7.5 15 17.5Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 330 510 210 240 247.5 propylene glycol 100 150 80 100 100Total 500 500 500 500 500

Example 3

Ingredients (mg) K L M N O Nicotine benzoate 5 17.5 7.5 15 17.5Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 320 510 270 240 197.5 glycerol 110 150 100 100 150 Total500 500 500 500 500

Example 4

Ingredients (mg) P Q R S T Nicotine benzoate 5 17.5 7.5 15 17.5Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 330 560 190 240 247.5 PEG 400 100 100 100 100 100 Total500 500 500 500 500

Example 5

Ingredients (mg) U V W X Y Nicotine polacrilex 5 17.5 7.5 15 17.5Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 300 460 170 240 147.5 β-cyclodextrin 130 200 200 100 200Total 500 500 500 500 500

Example 6

Ingredients (mg) Z AA BB CC DD Nicotine polacrilex 5 17.5 7.5 15 17.5Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 330 510 210 240 247.5 propylene glycol 100 150 80 100 100Total 500 500 500 500 500

Example 7

Ingredients (mg) EE FF GG HH II Nicotine polacrilex 5 17.5 7.5 15 17.5Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 320 510 270 240 197.5 glycerol 110 150 100 100 150 Total500 500 500 500 500

Example 8

Ingredients (mg) JJ KK LL MM NN Nicotine polacrilex 5 17.5 7.5 15 17.5Sunflower oil 15 52.5 22.5 45 35 Sodium bicarbonate 50 100 100 100 100Inulin LV 110 330 560 190 240 247.5 PEG 400 100 100 100 100 100 Total500 500 500 500 500

As demonstrated by the following data and FIGS. 1 to 8 , the disclosedcompositions are more effective in increasing the plasma level ofnicotine via oral delivery than providing nicotine alone in a carrier.The following animal study provides conclusive proof of this fact.

The disclosed animal studies were conducted utilizing the disclosedcompositions. Table I summarizes the Study design. Male Beagle dogs fromMarshall Bioresources were utilized for this study. Animals wereidentified by ear tattoo and cage label. The study was not blinded. Theanimals were healthy at the start of the study. Body weights wererecorded at each dosing time point. General health observations wererecorded at each dosing and sample collection time point for theduration of the study.

Dosing

Nicotine, 4 mg per pouch, was administered via buccal administration.Animals were anesthetized with propofol at a dose of 6 mg/kg, animalswere then intubated and maintained in an anesthetic state usingisoflurane at 1-5% and 2 L of oxygen flow. The pouch with test articlewas placed in the buccal space, rinsed with a small volume of water(0.5-1 mL). Every 5 minutes after placing the pouch the test articletest article in the buccal space, the isoflurane mask was removed andthe pouch gently squeezed. Special attention was taken to ensure salivadid not leak from the mouth. Following 30 minutes, the pouch testarticle was removed from the buccal space and the animal allowed torecover from anesthesia. All pouches were retained following dosing.Each pouch was placed in individual conical tube with the animal ID andpouch identification.

Test Compositions Nicotine Benzoate Control

TABLE I Ingredients % mg Nicotine benzoate 1.11 7 Inulin LV 110(pre-tested) 98.89 624 Total 100 631

Nicotine Benzoate Disclosed Composition

TABLE II Ingredients % mg Nicotine benzoate 1.37 8.6 Sunflower oil 4.0925.8 Sodium bicarbonate 13.72 86.6 Inulin LV 110 (pre-tested) 80.82 510Total 100 631

Nicotine Polacrilex Control

TABLE III Ingredients % mg Nicotine polacrilex 3.6 20 Glycerin 0.4 2.2Inulin LV 110 (pre-tested) 96.0 632.8 Total 100 555

Nicotine Polacrilex Disclosed Composition

TABLE IV Ingredients % mg Nicotine polacrilex 3.91 21.7 Sunflower oil13.04 72.6 Sodium bicarbonate 13.69 76.1 Glycerin 0.44 2.4 Inulin LV 110(pre-tested) 68.92 383.2 Total 100 556

As shown in the table below, Group 1 was administered the nicotinebenzoate control group. Group 2 was administered the disclosedcomposition comprising nicotine benzoate. Group 3 was administered thenicotine polacrilex control. Group 4 was administered the disclosecomposition comprising nicotine polacrilex. The actual amounts based onresults of potency testing was 3.12, 3.31, 3.48, and 3.79 mg per pouch,in Groups 1, 2,3, and 4, respectively

TABLE V Blood Test Dosing Dose Dose Sampling Group # Article Route N=(mg/pouch) Volume Time Points 1 Nicotine Buccal 10 631 N/A Pre-dose, 2,benzoate 4, 6, 8, 10, (Control) 15, 30, 45, 2 Nicotine Buccal 10 631 N/A60, and 120 benzoate minutespost 3 Nicotine Buccal 10 555 N/A dose*polacrilex (Control) 4 Nicotine Buccal 10 556 N/A polacrilex

Sample Collection, Preparation and Storage

Each blood sample (approx. 2000 μL) was collected from the jugular veinin a K2ETDA collection tube and gently inverted several time to mix. Thesamples were kept on ice until centrifugation at 4° C. for 5 minutes at3,000×g. Approximately 1000 μL plasma was separated by centrifugation.The resulting plasma samples were stored at −80 C until bioanalysis wasconducted.

Quantitative Plasma Sample Analysis

Plasma samples were extracted by protein precipitation and analyzedusing LC-MS/MS. Individual and Mean plasma concentrations and resultingpharmacokinetic parameters for nicotine are shown in Tables 4-7. Alldata are expressed as ng/mL of nicotine. Samples that were below thelimit of quantification (1.0 ng/mL in plasma) were excluded from thecalculation of mean values. Mean concentrations versus time data areplotted in FIGS. 1-8 .

Pharmacokinetic parameters were calculated from the time course of theplasma concentration. Pharmacokinetic parameters were determined withPhoenix WinNonlin (v8.0) software using a noncompartmental model. Themaximum plasma concentration (Cmax) and the time to reach maximum plasmaconcentration (tmax) after dosing were observed from the data. The areaunder the time concentration curve (AUC) was calculated using the lineartrapezoidal rule with calculation to the last quantifiable data point(AUC0-last), and with extrapolation to infinity (AUC∞) if applicable.Plasma half-life (t1/2) was calculated from 0.693/slope of the terminalelimination phase. Mean residence time, MRT, was calculated by dividingthe area under the moment curve (AUMC) by the AUC. Any samples below thelimit of quantitation (1.0 ng/mL plasma) were not used in thecalculation of mean values

Data

Pharmacokinetic Parameters and Plasma Concentrations (ng/mL) forNicotine after Buccal Administration of the Nicotine Benzoate ControlComposition Disclosed in TABLES VI and VII in Male Beagle Dogs (Group 1)

TABLE VI Animal number Sample time (hr) 1 2 3 4 5 0.0333 15.1 7.43 4.835.09 2.39 0.0666 18.7 24.9 46.4 9.37 9.00 0.1 19.3 27.0 50.0 9.5 13.70.122 21.5 30.7 301 20.5 19.6 0.167 94.1 32.1 54.3 50.3 20.0 0.25 50.634.0 55.4 192.4 25.4 0.5 50.9 42.6 55.9 88.9 62.8 0.75 49.1 121 94.247.4 46.9 1 73.3 49.8 33.9 41.1 38.6 2 12.8 7.05 5.4 12.1 9.17 Dose(mg/kg) 0.354 0.62 0.362 0.385 0.3 C_(max) (ng/mL) 94.1 121 94.2 192.462.8 t_(max) (hr) 0.167 0.75 0.75 0.250 0.5 t_(1/2) 0.547 ND² ND² 0.6140.516 MRT_(last) (hr) 0.827 0.792 0.691 0.65 0.815 AUC_(last) (hr ·ng/mL) 93.6 86.1 78.9 102.3 63.0 AUC_(∞)(hr · ng/mL) 104 ND² ND² 11369.9 AUC_(last)/D 264 238 218 266 210 (hr · kg · ng/mL/mg) AUC_(∞)/D 293ND² ND² 294 233 (hr · kg · ng/mL/mg) 1. AUC_(last)/D (hr · kg ·ng/mL/mg) and AUC_(∞)/D (hr · kg · ng/mL/mg) are dose normalized values.²Not determined because the line defining the terminal elimination phasehad an r² of <0.85.

TABLE VII Animal number Sample time (hr) 6 7 8 9 10 0.0333 15.4 4.4511.2 BLOQ³ 9.41 0.0666 17.0 10.0 181 2.32 38.5 0.1 21.3 21.3 33.2 6.840.6 0.122 31.4 28.4 34.0 16.4 ND² 0.167 33.4 29.0 34.9 35.3 53.7 0.2534.1 43.1 38.6 49.2 50.1 0.5 53.4 67.0 73.2 116.5 55.6 0.75 90.5 44.199.4 126.7 57.8 1 57.2 36.2 39.5 37.8 62.8 2 10.5 3.46 5.53 9.6 12.4Dose (mg/kg) 0.376 0.30 0.416 0.243 0.223 C_(max) (ng/mL) 90.5 67.0 99.4127 62.8 t_(max) (hr) 0.75 0.50 0.75 0.75 1.0 t_(1/2) ND² 0.326 ND² ND²ND² MRT_(last) (hr) 0.822 0.712 0.732 0.738 0.507 AUC_(last) (hr ·ng/mL) 87.4 63.1 82.5 100 89.9 AUC_(∞)(hr · ng/mL) ND² 64.7 ND² ND² ND²AUC_(last)/D 233 211 198 412 403 (hr · kg · ng/mL/mg) AUC_(∞)/D ND² 216ND² ND² ND² (hr · kg · ng/mL/mg) 1. AUC_(last)/D (hr · kg · ng/mL/mg)and AUC_(∞)/D (hr · kg · ng/mL/mg) are dose normalized values. 9. ²Notdetermined because the line defining the terminal elimination phase hadan r² of <0.85. ³BLOQ = below the limit of quantitation (1 ng/mL)

TABLE VIII provides the mean and standard deviation for the results ofAnimals 1-10.

TABLE VIII Sample time (hr) mean SD 0.0333 8.36 4.73 0.0666 19.6 14.70.1 24.3 13.7 0.122 25.3 6.55 0.167 43.7 21.0 0.25 57.3 48.4 0.5 66.724.8 0.75 77.7 32.3 1 47.0 13.3 2 8.79 3.28 Dose (mg/kg) 0.332 0.063C_(max) (ng/mL) 101 39.0 t_(max) (hr) 0.617 0.258 t_(1/2) 0.501 0.123MRT_(last) (hr) 0.759 0.062 AUC_(last) (hr · ng/mL) 84.7 13.5 AUC_(∞)(hr· ng/mL) 87.8 24.1 AUC_(last)/D 265 78.3 (hr · kg · ng/mL/mg) AUC_(∞)/D259 40.3 (hr · kg · ng/mL/mg)

FIG. 1 is a plot of the individual plasma concentrations (ng/mL) forNicotine versus time (hour) after buccal administration of the nicotinebenzoate control composition disclosed in TABLE I in male Beagle dogs.FIG. 2 is a plot of the mean plasma concentration (ng/mL) for Nicotineversus time (hour) after buccal administration of nicotine benzoatecontrol composition disclosed in TABLE I in male Beagle dogs.

Pharmacokinetic Parameters and Plasma Concentrations (ng/mL) forNicotine after Buccal Administration of pouches Containing the NicotineBenzoate Disclosed Composition in TABLES IX and X (4 mg) in Male BeagleDogs (Group 2)

TABLE IX Animal number Sample time (hr) 11 12 13 14 15 0.0333 132 50.025.6 38.8 107 0.0666 233 70.9 64.3 332 134 0.1 240 100 78.9 446 4120.122 247 105 88.7 349 413 0.167 253 117 98.8 258 136 0.25 350 486 113241 418 0.5 342 175 228 240 647 0.75 150 95.7 91.8 220 153 1 88.2 610478.1 83.3 82.4 2 33.0 30.9 21.8 37.0 32.4 Dose (mg/kg) 0.38 0.269 0.3310.429 0.413 C_(max) (ng/mL) 350 486 228 446 647 t_(max) (hr) 0.25 0.250.5 0.10 0.50 t_(1/2) 0.606 0.823 0.583 0.554 0.601 MRT_(last) (hr)0.603 0.597 0.710 0.632 0.55 AUC_(last) (hr · ng/mL) 296 220 173 2800397 AUC_(∞)(hr · ng/mL) 325 257 191 309 425 AUC_(last)/D (hr · 778 819523 652 961 kg · ng/mL/mg) AUC_(∞)/D (hr · 854 956 578 720 1029 kg ·ng/mL/mg) 1. AUC_(last)/D (hr · kg · ng/mL/mg) and AUC_(∞)/D (hr · kg ·ng/mL/mg) are dose normalized values. 2. Not determined because the linedefining the terminal elimination phase had an r² of <0.85.

TABLE X Animal number Sample time (hr) 16 17 18 19 20 0.0333 34.9 14.3556 6.85 5.63 0.0666 18.2 48.4 368 27.2 12.8 0.1 117 73.5 105 384 57.90.122 125 88.1 124 788 73.4 0.167 133 89.3 130 703 76.3 0.25 135 156 131231 79.0 0.5 137 225 150 227 81.4 0.75 156 108 70 204 197 1 46.4 107.653.4 81.0 52.7 2 17.6 23.4 11.9 21.6 16.3 Dose (mg/kg) 0.380 0.318 0.3410.290 0.301 C_(max) (ng/mL) 156 225 150 788 197 t_(max) (hr) 0.750 0.500.50 0.133 0.750 t_(1/2) ND² 0.530 0.481 0.418 ND² MRT_(last) (hr) 0.6640.732 0.631 0.554 0.757 AUC_(last) (hr · ng/mL) 152 201 135 289 133AUC_(∞)(hr · ng/mL) ND² 219 143 302 ND² AUC_(last)/D 400 632 395 997 443(hr · kg · ng/mL/mg) AUC_(∞)/D ND² 688 420 1042 ND² (hr · kg ·ng/mL/mg) 1. AUC_(last)/D (hr · kg · ng/mL/mg) and AUC_(∞)/D (hr · kg ·ng/mL/mg) are dose normalized values. ²Not determined because the linedefining the terminal elimination phase had an r² of <0.85. 3. BLOQ =below the limit of quantitation (1 ng/mL)

TABLE XI provides the mean and standard deviation for the results ofAnimals 11-21.

TABLE XI Sample time (hr) mean SD 0.0333 46.1 44.6 0.0666 108 108 0.1201 156 0.122 240 226 0.167 207 198 0.25 234 140 0.5 245 158 0.75 14552.1 1 73.4 19.3 2 24.6 8.83 Dose (mg/kg) 0.345 0.054 C_(max) (ng/mL)367 220 t_(max) (hr) 0.423 0.232 t_(1/2) 0.574 0.119 MRT_(last) (hr)0.643 0.072 AUC_(last) (hr · ng/mL) 228 86.2 AUC_(∞)(hr · ng/mL) 27188.5 AUC_(last)/D 660 223 (hr · kg · ng/mL/mg) AUC_(∞)/D 786 223 (hr ·kg · ng/mL/mg)

FIG. 3 depicts the individual plasma concentrations (ng/mL) for Nicotineversus time (hour) after buccal administration of the disclosed nicotinebenzoate composition disclosed in Table II (4 mg) in male Beagle dogs.FIG. 4 shows the mean plasma concentration (ng/mL) for Nicotine versustime (hour) after buccal administration of the disclosed compound inTable II (4 mg) in male Beagle dogs.

Pharmacokinetic and Individual Plasma Concentrations (ng/mL) forNicotine versus Time (hour) after Buccal Administration of NicotinePolacrilex Control Composition Disclosed in TABLES XII and XIII (4 mg)in Male Beagle Dogs (Group 3)

TABLE XII Animal number Sample time (hr) 21 22 23 24 25 0.0333 18.3 1.36BLOQ BLOQ 1.146 0.0666 26.3 1.73 1.55 3.08 2.76 0.1 27.1 2.04 1.80 4.025.64 0.122 29.2 3.24 1.92 6.40 9.68 0.167 52.7 3.54 2.44 9.00 10.1 0.2529.3 4.76 7.10 9.54 11.7 0.5 27.3 10.1 19.8 12.0 18.4 0.75 7.34 10.911.6 27.6 31.3 1 4.60 7.18 10.4 8.36 19.7 2 1.32 1.61 1.7 1.34 2.59 Dose(mg/kg) 0.290 0.303 0.264 0.266 0.317 C_(max) (ng/Ml) 52.7 10.9 19.827.6 31.3 t_(max) (hr) 0.167 0.750 0.50 0.750 0.750 t_(1/2) 0.518 ND²0.423 ND² ND² MRT_(last) (hr) 0.468 0.818 0.787 0.749 0.851 AUC_(last)(hr · ng/Ml) 23.5 11.8 16.7 18.4 22.2 AUC_(∞)(hr · ng/Ml) 24.5 ND² 17.7ND² ND² AUC_(last)/D 81.0 39.0 63.3 69.2 81.4 (hr · kg · ng/Ml/mg)AUC_(∞)/D 84.4 ND² 67.2 ND² ND² (hr · kg · ng/Ml/mg) 1. AUC_(last)/D (hr· kg · ng/Ml/mg) and AUC_(∞)/D (hr · kg · ng/Ml/mg) are dose normalizedvalues. ²Not determined because the line defining the terminalelimination phase had an r² of <0.85.

TABLE XIII Animal number Sample time (hr) 26 27 28 29 30 0.0333 BLOQ1.60 BLOQ BLOQ BLOQ 0.0666 BLOQ 2.25 NS⁴ BLOQ 3.07 0.1 1.33 7.51 2.891.31 3.15 0.122 1.74 8.62 8.35 2.71 4.02 0.167 5.14 6.56 31.7 9.38 4.910.25 7.69 9.36 52.2 9.64 14.4 0.5 15.4 10.4 35.5 11.9 16.0 0.75 16.010.0 34.0 30.2 45.4 1 18.5 9.1 15.9 20.5 21.3 2 1.95 1.70 2.11 2.29 1.60Dose (mg/kg) 0.272 0.363 0.400 0.290 0.484 C_(max) (ng/mL) 18.5 10.452.2 30.2 45.4 t_(max) (hr) 1.00 0.50 0.250 0.750 0.750 t_(1/2) ND²0.465 0.320 ND² ND² MRT_(last) (hr) 0.851 0.778 0.645 0.849 0.802AUC_(last) (hr · ng/mL) 22.2 14.2 39.4 26.8 32.5 AUC_(∞)(hr · ng/mL) ND²15.4 40.4 ND² ND² AUC_(last)/D 81.4 39.2 98.4 92.4 67.3 (hr · kg ·ng/mL/mg) AUC_(∞)/D ND² 42.3 100.8 ND² ND² (hr · kg · ng/mL/mg) 1.AUC_(last)/D (hr · kg · ng/mL/mg) and AUC_(∞)/D (hr · kg · ng/mL/mg) aredose normalized values. 9. ²Not determined because the line defining theterminal elimination phase had an r² of <0.85. 3. BLOQ = below the limitof quantitation (1 ng/mL)

TABLE XIV provides the mean and standard deviation for the results ofAnimals 21-30.

TABLE XIV Sample time (hr) mean SD 0.0333 5.58 8.48 0.0666 5.82 9.05 0.15.68 7.80 0.122 7.58 8.13 0.167 13.5 16.1 0.25 15.6 14.6 0.5 17.7 8.170.75 22.4 12.9 1 13.6 6.27 2 1.82 0.412 Dose (mg/kg) 0.325 0.071 C_(max)(ng/mL) 29.9 15.8 t_(max) (hr) 0.617 0.258 t_(1/2) 0.431 0.084MRT_(last) (hr) 0.756 0.117 AUC_(last) (hr · ng/mL) 23.5 8.66 AUC_(∞)(hr· ng/mL) 24.5 11.3 AUC_(last)/D 72.3 21.0 (hr · kg · ng/mL/mg) AUC_(∞)/D73.7 25.0 (hr · kg · ng/mL/mg)

FIG. 5 shows the individual plasma poncentrations (ng/mL) for Nicotineversus time (hour) after buccal administration of the nicotinepolacrilex control composition disclosed in TABLE III (4 mg) in maleBeagle dogs (Group 3). FIG. 6 displays the mean plasma concentration(ng/mL) for Nicotine versus time (hour) after buccal administration ofthe nicotine polacrilex control composition disclosed in TABLE III (4mg) in Male Beagle dogs (Group 3)

Pharmacokinetic Parameters and Plasma Concentrations (ng/mL) forNicotine after Buccal Administration of Pouches Containing the NicotinePolacrilex Disclosed Composition in TABLES XV and XVI (4 mg) in MaleBeagle Dogs (Group 4)

TABLE XV Animal number Sample time (hr) 31 32 33 34 35 0.0333 5.50 18.9192 5.26 2.05 0.0666 27.5 19.6 374 44.3 10.7 0.1 36.1 30.9 874 51.0 44.50.122 51.4 44.2 893 63.2 50.5 0.167 53.6 48.8 609 66.3 74.3 0.25 68.477.8 207 86.2 100 0.5 120 167 175 118 176 0.75 105 144 149 74.4 92.0 145.1 60.8 76.2 59.2 67.2 2 9.77 18.2 18.7 20.6 20.6 Dose (mg/kg) 0.2420.304 0.327 0.314 0.304 C_(max) (ng/mL) 120 167 893 118 176 t_(max) (hr)0.500 0.500 0.133 0.500 0.500 t_(1/2) 0.387 0.455 0.451 0.511 0.581MRT_(last) (hr) 0.709 0.749 0.485 0.731 0.744 AUC_(last) (hr · ng/mL)108 144 286 116 144 AUC_(∞)(hr · ng/mL) 113 156 298 126 161 AUC_(last)/D446 476 874 369 475 (hr · kg · ng/mL/mg) AUC_(∞)/D 468 515 912 403 531(hr · kg · ng/mL/mg) 1. AUC_(last)/D (hr · kg · ng/mL/mg) and AUC_(∞)/D(hr · kg · ng/mL/mg) are dose normalized values. 2. Not determinedbecause the line defining the terminal elimination phase had an r² of<0.85.

TABLE XVI Animal number Sample time (hr) 36 37 38 39 40 0.0333 8.03 9.8313.2 11.1 3.67 0.0666 94.4 16.8 320 65.8 9.77 0.1 401 37.9 72.3 255 21.20.122 638 53.3 81.7 238 28.6 0.167 817 56.1 418 94.5 36.5 0.25 595 73.7184 331 70.4 0.5 225 149 172 217 139 0.75 108 267 160 74 57.7 1 59.073.7 85.0 39.7 43.7 2 16.4 16.5 21.1 11.0 8.69 Dose (mg/kg) 0.311 0.3580.345 0.336 0.319 C_(max) (ng/mL) 817 267 418 331 139 t_(max) (hr) 0.1670.750 0.167 0.250 0.500 t_(1/2) 0.481 ND² 0.473 0.475 0.449 MRT_(last)(hr) 0.443 0.795 0.662 0.495 0.700 AUC_(last) (hr · ng/mL) 313 183 209193 97 AUC_(∞)(hr · ng/mL) 325 ND² 223 200 102 AUC_(last)/D 1008 511 605574 303 (hr · kg · ng/mL/mg) AUC_(∞)/D 1044 ND² 647 596 321 (hr · kg ·ng/mL/mg) 1. AUC_(last)/D (hr · kg · ng/mL/mg) and AUC_(∞)/D (hr · kg ·ng/mL/mg) are dose normalized values. 9. ²Not determined because theline defining the terminal elimination phase had an r² of <0.85. 3. BLOQ= below the limit of quantitation (1 ng/mL).

TABLE XVII provides the mean and standard deviation for the results ofAnimals 31-40.

TABLE XVII Sample time (hr) mean SD 0.0333 27.0 58.3 0.0666 73.6 116 0.1182 273 0.122 214 302 0.167 242 297 0.25 179 169 0.5 166 36.2 0.75 12361.3 1 60.9 15.0 2 16.5 5.66 Dose (mg/kg) 0.316 0.032 C_(max) (ng/mL)345 287 t_(max) (hr) 0.397 0.204 t_(1/2) 0.474 0.052 MRT_(last) (hr)0.651 0.127 AUC_(last) (hr · ng/mL) 1799 73.7 AUC_(∞)(hr · ng/mL) 19079.6 AUC_(last)/D 564 219 (hr · kg · ng/mL/mg) AUC_(∞)/D 604 235 (hr ·kg · ng/mL/mg)

FIG. 7 shows the individual plasma poncentrations (ng/mL) for Nicotineversus time (hour) after buccal administration of the nicotinepolarcilex composition disclosed in TABLE VI (4 mg) in male Beagle dogs(Group 4). FIG. 8 discloses the mean plasma concentration (ng/mL) forNicotine versus time (hour) after buccal administration of the nicotinepolarcrilex composition disclosed in TABLE VI (4 mg) in male Beagle dogs(Group 4).

Procedures Analytical Stock Solution Preparation

Analytical stock solutions (1.00 mg/mL of the free drug) was prepared inwater.

Standard Preparation

Standards were prepared in blank male Beagle dog plasma. Workingsolutions were prepared in 50:50 acetonitrile:water. Working solutionswere then added to plasma to make calibration standards to finalconcentrations of 2000, 1000, 500, 250, 100, 50, 10, 5, 2 and 1 ng/mL.Standards were treated identically to the study samples.

Sample Extraction

Plasma samples were manually extracted via precipitation withacetonitrile in a 96-well plate.

Step Procedure 1 Standards: Add 10 μL of appropriate working solution to50 μL of blank plasma. Blanks: Add 10 μL of 50:50 (v:v)acetonitrile:water to 50 μL of blank plasma. Samples: Add 10 μL of 50:50(v:v) acetonitrile:water to 50 μL of plasma study sample. 2 Add 150 μLof acetonitrile containing 20 ng/mL nicotine-d₄ in acetonitrile as aninternal standard. Cap and vortex. 3 Centrifuge samples at 4° C., at3000 rpm for 5 minutes. 4 Transfer 125 μL supernatant and analysis byLC-MS/MS

HPLC Conditions

Instrument: Waters Acquity UPLC

Column: Waters Phenyl BEH 1.7 μm, 2.1×50 mm

Aqueous Reservoir (A): 10 mm Ammonium bicarbonate in water, pH 9.5

Organic Reservoir (B): Acetonitrile

Gradient Program

Gradient Time (min.) Curve % A % B 0.00 6 90 10 0.20 6 90 10 1.00 6 1090 1.50 6 10 95 1.51 6 90 10 2.00 6 90 10

Flow Rate: 600 μL/min

Injection Volume: 3 μL

Run Time: 2.0 min

Column Temperature: 30° C.

Sample Temperature: 4° C.

Strong Autosampler Wash: 1:1:1:1 (v:v)acetonitrile:methanol:isopropanol:water

Weak Autosampler Wash: 50:50 (v:v) methanol:water

Mass Spectrometer Conditions

Instrument: Waters Xevo TQ-MS

Interface: Electrospray

Mode: Multiple Reaction Monitoring (MRM)

Desolvation Gas: 1000 L/hr

Cone Gas: 100 L/hr

Collision Gas: 0.25 mL/min

Desolvation Temp: 500° C.

Capillary Voltage: 2.5 kV

While particular embodiments of the present disclosure have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the disclosure. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this disclosure.

What is claimed is:
 1. A composition comprising: a) from about 0.25% toabout 6% by weight of nicotine, a nicotine salt, nicotine in combinationwith a resin, or mixtures thereof; b) from about 1% to about 20% byweight of an edible oil; c) from about 5% to about 20% by weight ofsodium bicarbonate; and d) the balance one or more carriers.
 2. Thecomposition according to claim 1, comprising nicotine.
 3. Thecomposition according to claim 1, comprising a nicotine salt.
 4. Thecomposition according to claim 3, wherein the nicotine salt is chosenfrom, and polymer resins of containing nicotine. Non-limiting examplesof nicotine salts includes nicotine benzoate, nicotine lactate, nicotinemalate, nicotine ditartrate, nicotine salicylate, nicotine citrate andnicotine levulinate.
 5. The composition according to claim 1, comprisingnicotine in combination with a resin.
 6. The composition according toclaim 5, wherein the nicotine in combination with a resin is nicotinepolacrilex or nicotine resinate.
 7. The composition according to claim1, wherein the edible oil is chosen from sunflower oil, coconut oil,canola oil, palm oil, soybean oil, corn oil, safflower oil, or peanutoil.
 8. The composition according to claim 1, wherein the carrier ischosen from inulin, microcrystalline cellulose, galactogen, cellulose,chitin, pectin, psyllium, guar, hemicellulose, potato starch, orpartially hydrolyzed polysaccharides
 9. The composition according toclaim 1, wherein the carrier is chosen from sorbitol, erythritol,xylitol, lactitol, maltitol, mannitol, hydrogenated starch hydrolysates,or isomaltose.
 10. The composition according to claim 1, furthercomprising glycerol, propylene glycol, (3-cyclodextrin, propylene glycol400 (PEG 400), or mixtures thereof.
 11. The composition according toclaim 1, wherein the ratio of nicotine, a nicotine salt, nicotine incombination with a resin to the edible oil is from about 1:1 to about1:4.
 12. A composition, comprising: a) from about 0.5 mg to about 50 mgby weight of nicotine, a nicotine salt, nicotine in combination with aresin, or mixtures thereof; b) from about 10 mg to about 160 mg byweight of an edible oil; and c) from about 25 mg to about 300 mg byweight of sodium bicarbonate.
 13. The composition according to claim 12,comprising from 15 mg to about 40 mg by weight of nicotine, a nicotinesalt, nicotine in combination with a resin, or mixtures thereof.
 14. Thecomposition according to claim 12, further comprising a carrier chosenfrom inulin, microcrystalline cellulose, galactogen, cellulose, chitin,pectin, psyllium, guar, hemicellulose, potato starch, partiallyhydrolyzed polysaccharides, from sorbitol, erythritol, xylitol,lactitol, maltitol, mannitol, hydrogenated starch hydrolysates, orisomaltose.
 15. The composition according to claim 12, furthercomprising glycerol, propylene glycol, (3-cyclodextrin, propylene glycol400 (PEG 400), or mixtures thereof.
 16. The composition according toclaim 12, comprising: a) from about 8.6 mg to about 21.7 mg of nicotine,a nicotine salt, nicotine in combination with a resin, or mixturesthereof; b) from about 25.8 to about 72.6 mg of sunflower oil; and c)from about 76.1 mg to about 86.6 mg of sodium bicarbonate.
 17. A kit,comprising: A) a liquid permeable pouch comprising a non-nicotinecomposition comprising: a) one or more delivery control agents; and b) abulking agent; and B) a base nicotine delivery composition comprising:a) nicotine, a nicotine salt, nicotine in combination with a resin, ormixtures thereof; b) sunflower oil; c) sodium bicarbonate; and d) thebalance one or more carriers.
 18. The kit according to claim 17, whereinthe liquid permeable pouch comprises wheat fibers, oat fibers, peafibers, rice fiber, maize fibers, oat fibers, tomato fibers, barleyfibers, rye fibers, sugar beet fibers, buckwheat fibers, potato fibers,cellulose fibers, apple fibers, cocoa fibers, cellulose fiber, powderedcellulose, bamboo fibers, bran fibers or combinations thereof.
 19. Thekit according to claim 17, comprising: B) from about 70 mg to about 510mg of an active base delivery system, comprising: a) from about 5 mg toabout 50 mg by weight of nicotine benzoate; b) from about 15 mg to about160 mg by weight of sunflower oil; c) from about 50 mg to about 300 mgby weight of sodium bicarbonate; d) from about 350 mg to about 1500 mgof one or more carriers; and e) the balance one or more delivery controlagents
 20. The kit according to claim 17, wherein the carrier is chosenfrom inulin, microcrystalline cellulose, galactogen, cellulose, chitin,pectin, psyllium, guar, hemicellulose, potato starch, or partiallyhydrolyzed polysaccharides, sorbitol, erythritol, xylitol, lactitol,maltitol, mannitol, hydrogenated starch hydrolysates, or isomaltose.